A foam is a multiphase mixture comprising bubbles of a gas phase that are separated by a liquid or solid layer (a film). Pilpel N., Foams in pharmacy, Endeavour 9: 87-91 (1985); Durian, D. J. and Weitz, D. A., “Foams” in Kirk-Othmer Encyclo. Chem. Tech., 4th ed., 11: 783-805 (1994). Liquid-based foams are dynamic systems that eventually collapse or break to release the gas phase. A foam's collapsibility or breakability depends on numerous physical properties of its components, such as the liquid phase's viscosity and surface tension, the gas phase's pressure and bubble size, and the film's elasticity.
To persist for more than a short period, a foam preferably includes at least one foaming agent such as a protein or surfactant. Surfactants stabilize the foam, e.g., by inhibiting bubble coalescence. Zhao, Y.; Brown, M. B.; Jones, S. J., Pharmaceutical foams: are they the answer to the dilemma of topical nanoparticles?, Nanomedicine, in press (2010).
As discussed in WO2009/090558, the types of topical foam vehicles include aqueous foams, such as commonly available shaving foams; hydroalcoholic foams; emulsion-based foams, comprising oil and water components; and oleaginous foams, which comprise high levels of oil. Lower alcohol compounds may increase penetration, but may also dry the skin and may cause stinging if applied to wounds or sores. Oily components may be emollients, moistening the skin, but may also leave an unpleasant greasy residue.
Some foams are long-lasting (e.g., shaving creams or gels). Other foams are quick-breaking and collapse soon after application, which can allow more rapid absorption of the foam's active agent. However, if the foam breaks too quickly, it will be difficult to apply. Quick-breaking foams may be destabilized by body heat (thermolabile) or by force (labile to mechanical stress), which allows easy spreading over the site of application.
Mere combination of basic ingredients does not automatically produce foams suitable for pharmaceutical or cosmetic use. Small changes in the foam base, such as the addition of active ingredients or co-solvents, may destabilize a foam. Similarly, selection within a group of ingredients may provide a foam or class of foams that provides unpredictably superior properties.
For example, DMSO is a polar aprotic solvent with lower surface tension than water. DMSO has penetration-enhancing properties that make it an attractive as a solvent, but it is difficult to foam. A DMSO-based foam would likely provide improved penetration of its active ingredient in addition to the other advantages of a foam.
Although a foam's properties can be difficult to predict, properties such as collapsibility or stiffness are crucial for the foam's intended use. For example, a pharmaceutical foam for internal application must sometimes persist for hours or days to release an active agent slowly. A pharmaceutical foam for topical application to skin must break down more quickly, but not so quickly that the liquid or solid phase will drip off the skin before absorption of sufficient active agent.
Qualities such as foam stability, easiness to spread, and appropriate breakability upon application to the skin or joint are desirable features. These characteristics can be measured by conducting foam formation and foam collapsibility experiments. Foam formation (foam height vs. time), for example, is predictive of the generation of a sprayable/spreadable foam. The rate of collapsibility is an important property in the appropriate administration of the foam.
Many foams are generated by dispensing a foam base in combination with a dissolved, gaseous propellant that expands upon release from a container to produce the foam's bubbles (e.g., those disclosed in WO 2010/125470). However, propellant-based foams take longer to collapse as compared to quick-breaking aqueous foams and as such may not be useful in certain applications. Manufacturing a propellant-based composition can also be more costly and difficult, and the associated canisters can harm the environment. Additionally, there is an increased risk in handling and transporting pressurized canisters due to the dangers associated with their explosive properties. It is therefore preferable to develop a composition comprising DMSO that is foamable in the absence of a propellant.
Pharmaceutical foams have been used in wound and burn dressings, contraception, and topical drug delivery. They are easy to apply uniformly to skin, less messy than cream or liquid dosage forms, and less irritating to sensitive or abraded skin. Zhao, Y. et al., Id. The superior properties of foams may enhance patient compliance. The dispensing means of a foam formulation can help to prevent contamination of the container during application. For at least these reasons, foams are attractive dosage forms for topically absorbable active agents.
Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. Symptoms include joint pain and impaired movement. OA is one of the leading causes of disability worldwide and a major financial burden to health care systems. It is estimated to affect over 15 million adults in the United States alone. See Boh L. E. Osteoarthritis. In: DiPiro J. T., Talbert R. L., Yee G. C., et al., editors. Pharmacotherapy: a pathophysiological approach. 4th ed. Norwalk (CT): Appleton & Lange, pp. 1441-59 (1999).
Oral non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the management of OA. Oral NSAIDs are also commonly used in the management of pain associated with injuries such as minor strains, sprains and contusions. These drugs are thought to exert their analgesic effect by impeding the production of signaling molecules called prostaglandins through inhibition of the cyclooxygenase (“COX”) enzyme. The COX enzyme has two isoforms, COX-1 and COX-2. Traditional NSAIDs inhibit both isoforms of the COX enzyme, while the selective COX-2 (coxib) class of NSAIDs preferentially inhibits COX-2.
NSAIDs have analgesic, anti-inflammatory, and antipyretic effects and are useful in reducing pain and inflammation. They are, however, associated with serious potential side effects including nausea, vomiting, peptic ulcer disease, and gastrointestinal (GI) hemorrhage. Although selective COX-2 inhibitors produce fewer gastrointestinal side effects, they may increase the risk of thrombotic events (e.g., stroke or heart attack). Because of this potential side effect, most of the selective COX-2 inhibitors have been withdrawn from the market.
Topical NSAIDs offer the possibility of achieving local therapeutic benefit while reducing or eliminating the risk of systemic side effects. Difficulties in topical NSAID treatment of OA or minor injuries partially arise from the difficulty associated with delivering a therapeutically effective dose of the NSAID through the skin in a manner that makes the treatment itself tolerable. It is generally believed that clinical efficacy in OA requires absorption of the active ingredient and its penetration in sufficient quantities into underlying inflamed tissues including the synovium and synovial fluid of joints. See Rosenstein, Topical agents in the treatment of rheumatic disorders, Rheum. Dis. Clin North Am., 25: 899-918 (1999).
Various factors can affect the absorption rates and penetration depth of topical pharmaceutical preparations, including the nature of the active ingredient, the nature of the vehicle, the pH, and the relative solubility of the active in the vehicle versus the skin (Ostrenga J. et al., Significance of vehicle composition I: relationship between topical vehicle composition, skin penetrability, and clinical efficacy, Journal of Pharmaceutical Sciences, 60: 1175-1179 (1971)). More specifically, drug attributes such as solubility, size and charge, as well as vehicle attributes such as the drug dissolution rate, spreadability, adhesion, and ability to alter the membrane permeability can each have significant effects on permeability. The skin barrier also can be compromised by physical methods, such as iontophoresis, ultrasound, electroporation, heat, and microneedles.
Topical NSAIDs take various forms such as liquids, gels, ointments and salves. Pharmaceutical foams are formed from the dispersion of a gas phase in a second immiscible liquid or solid phase. Pharmaceutical foams have been used in wound and burn dressings, contraception and topical skin delivery. The collapsibility or breakability of a pharmaceutical foam is often unpredictable and follows no particular theory. However, the feature of collapsibility or stiffness of a foam is crucial for many uses.
In light of the foregoing, there is a need for a topical DMSO foam formulation such as a topical NSAID foam suitable for long-term use in the treatment of OA. A diclofenac or ibuprofen foam would be especially useful. The challenge has been to develop a formulation that will deliver the active agent to the underlying tissue in sufficient concentration to treat a disorder, possibly on a long-term basis, while still providing a foam with an appropriate collapsibility or breakability. The present invention satisfies these and other needs.